For Patients With Newly Diagnosed GBM Having Unmethylated MGMT Expression

Trial Summary

Official Title

An Open Label Trial of Dianhydrogalactitol (VAL-083) and Radiation Therapy in Treatment of Newly Diagnosed GBM Patients With An Unmethylated Promoter of the Methylguanine-DNA Methyltransferase (MGMT) Gene

Status

Recruiting

Condition

Glioma, Glioblastoma, Glioblastoma Multiforme, GBM, Brain Cancer

Actual Start Date

September 30, 2017

Estimated Primary Completion Date

February 2019

About the Trial

The study drug, dianhydrogalactitol (VAL 083) is a bi-functional N7 DNA alkylating agent which has demonstrated cytotoxic activity that is independent of chemo-resistance due to expression of MGMT. This makes VAL-083 an ideal candidate to treat patients who are unlikely to respond to temozolomide due to MGMT expression in their GBM. Furthermore, VAL-083 acted as a radio-sensitizer at low (1 - 2.5μM) concentrations in all GBM cultures tested.

VAL-083 has been studied extensively in the United States by the National Cancer Institute. The NCI studies suggested that VAL-083 appeared to have activity in some types of cancer (lung and brain), including GBM; however, further VAL-083 research was not pursued in the US due to an increased focus on targeted biologic therapies during that era. VAL-083 has also been studied in the People's Republic of China, where it is currently approved and marketed for treatment of chronic myeloid leukemia and lung cancer. At present, VAL-083 is being studied in clinical trials in the United States as a third-line treatment option for patients with recurrent GBM following failure of surgery, radiation therapy, temozolomide and bevacizumab. Interim results support safety of VAL-083 in this population; to date, a regimen of 40mg/m2/d x 3 days IV in a 21 day cycle has been confirmed to be safe and well tolerated.

This phase 2, open-label, single arm study will be conducted in a dose-escalation cohort scheme to confirm the optimal dose of VAL-083, when administered concurrently with radiation therapy. Dose escalation will proceed in three sequential cohorts, consisting of patients receiving VAL-083 at 20, 30 and 40 mg/m2/d x 3 every 21 days.

This trial will be conducted in 2 parts. Part 1 will consist of 1) a 42-day induction period, during which patients will receive VAL-083 while undergoing radiation treatment at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks (for a total dose of 60 Gy), followed by 2) adjuvant maintenance therapy with VAL-083 alone, administered daily x 3 IV every 3 weeks at the same assigned dose, for a maximum of 8 maintenance cycles. Part 2 will comprise an expansion phase, in which VAL-083 will be studied in up to 20 additional subjects. The dose of VAL-083 that will be studied in Part 2 will be determined from Part 1.

In both parts of the study, a pharmacokinetic study may be conducted at treatment Cycle 1 Day 1, in consenting patients. For patients consenting to CSF collection by lumbar puncture, a CSF sample will be obtained after completion of the Cycle 1, Day 3 VAL-083 infusion. These patients will also have a blood sample taken for VAL-083 plasma level after completion of drug infusion.

Response parameters will be evaluated according to the Response Assessment in NeuroOncology (RANO).

Detailed Info

Brief Summary

The purpose of this Phase 2, open-label, single-arm study is to determine the safety and the
maximal tolerated dose (MTD) of VAL-083 in combination with a standard of care radiation
regimen when used to treat newly diagnosed GBM in patients with unmethylated promoter of the
methylguanine-DNA methyltransferase (uMGMT) gene. Pharmacokinetic (PK) properties will be
explored and tumor responses to treatment will be evaluated.

Gender

Age

Karnofsky Score

Inclusion Criteria

Tumor tissue specimens from the GBM surgery or open biopsy must be available for MGMT gene promoter status analysis and central pathology review.

Documented unmethylated MGMT gene promoter status

Males or females ≥18< 70 years of age.

Interval of ≥2 weeks but ≤7 weeks after surgery or biopsy before first administration of study treatment.

Cranial MRI must have been performed within 21 days of study entry and MRI must be used throughout the period of protocol treatment for tumor measurement. If the surgical procedure was a resection, cranial MRI performed within 72 hours of resection is preferred

Stable or decreasing dose of steroids for ≥5 days prior to randomization.

Karnofsky performance score ≥ 70%

Patients must begin treatment with VAL-083 chemotherapy no sooner than 2 weeks and no later than 4 weeks from the diagnostic surgery.

History of malignancy. Subjects with curatively treated cervical carcinoma in situ or basal cell carcinoma of the skin, or subjects who have been free of other malignancies for ≥5 years are eligible for this study.

History of coagulation disorder associated with bleeding or recurrent thrombotic events.

Concurrent illness, including severe infection, which may jeopardize the ability of the subject to receive the procedures outlined in this protocol with reasonable safety.

Subject is pregnant (positive serum beta human chorionic gonadotropin [b-HCG] test at screening) or is currently breast-feeding, anticipates becoming pregnant/ impregnating their partner during the study or within 6 months after study participation, or subject does not agree to follow acceptable methods of birth control, such as hormonal contraception, intra-uterine pessar, condoms or sterilization, to avoid conception during the study and for at least 6 months after receiving the last dose of study treatment.

Current alcohol dependence or drug abuse.

Known hypersensitivity to the study treatment.

Legal incapacity or limited legal capacity.

Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such.

Frequently Asked Questions

This clinical trial is being done to determine the safety and the maximal tolerated dose (MTD) of VAL-083 in combination with a standard of care radiation regimen when used to treat newly diagnosed GBM in patients with unmethylated promoter of the methylguanine-DNA methyltransferase (uMGMT) gene. Pharmacokinetic (PK) properties will be explored and tumor responses to treatment will be evaluated.

This clinical trial has certain criteria that a person has to meet to determine if they can participate. After you have discussed the trial with your doctor, specific tests will be done to see if you qualify for this study.

The total number of patients enrolled in this clinical trial will be 30 subjects. This trial will be conducted in 2 parts. Part 1 will consist of 1) a 42-day induction period, during which patients will receive VAL-083 while undergoing radiation treatment at a dose of 2 Gy per fraction given once daily five days per week (Monday through Friday) over a period of six weeks (for a total dose of 60 Gy), followed by 2) adjuvant maintenance therapy with VAL-083 alone, administered daily x 3 IV every 3 weeks at the same assigned dose, for a maximum of 8 maintenance cycles. Part 2 will comprise an expansion phase, in which VAL-083 will be studied in up to 20 additional subjects. The dose of VAL-083 that will be studied in Part 2 will be determined from Part 1.

The safety and efficacy of the investigational use of this product has not been determined. There is no guarantee that the investigational use listed will be filed with and/or approved for marketing by a regulatory agency.

The safety and efficacy of the investigational use of this product has not been determined. There is no guarantee that the investigational use listed will be filed with and/or approved for marketing by a regulatory agency.